37-OR: Distinct Functional Beta-Cell Subpopulations in Intact Islets of Langerhans

Glucose-stimulated insulin secretion is driven by the coordinated Ca²⁺ response in pancreatic islets following glucose elevation. In mouse islets, spatial and temporal Ca²⁺ dynamics are disproportionally controlled by subpopulations of β-cells, as identified by optogenetics. It is unknown which factors underlie this functional heterogeneity of β-cells in intact islets. Here, we tested if distinct β-cell subpopulations may be identified based on Ca²⁺ response to glucose elevation, and if their Ca²⁺ uptake efficiency, metabolic activity and electrical coupling are significantly different. We used MIP-CreER GCaMP6s mouse model which expresses Ca²⁺-sensitive GFP specifically in β-cells. We performed simultaneous Ca²⁺ dynamics and metabolic activity (NADH) response to [2-11] mM glucose elevation, along with gap junction permeability measurements in individual islets. We observed three functional subpopulations of β-cells distinct from an islet average: cells with 1) the fastest response to glucose elevation (1^st responders); 2) the fastest 2^nd phase oscillatory Ca²⁺ response (wave-initiators); and 3) the non-coordinated Ca²⁺ oscillations (un-coordinated). While 1^st responders and wave-initiators were in different sub-regions of the islet, both subpopulations accumulated more Ca²⁺ during initial Ca²⁺ elevation (p=0.0403, p=0.0101) compared to the islet-average. Wave-initiators were more metabolically active (p=0.0223). The un-coordinated cells accumulated less Ca²⁺ (p<0.001) and were less metabolically active (p=0.0296). Gap junction permeability was not significantly different between subpopulations.

In conclusion, the 1^st phase Ca²⁺ uptake and 2^nd phase Ca²⁺ oscillations emerge in spatially- and metabolically-distinct subregions of the islet. This is likely due to increased metabolic activity of the β-cells in these regions which leads to greater membrane depolarization and thus, disproportionately enhances the islet Ca²⁺response. (NIH R01 DK102950 R01 DK106412)